High Throughput Screen for Small Molecule Probes for Neural Network Development

用于神经网络开发的小分子探针的高通量筛选

• 批准号: 8190952
• 负责人: Richard L Huganir
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190952
• 关键词: Animals; Autistic Disorder; Automation; Biological; Biological Assay; Biological Neural Networks; Brain; Chemicals; Collection; Data; Data Set; Defect; Dendrites; Development; Disease; Dose; Drug Delivery Systems; Epilepsy; Equilibrium; Genes; Genetic; Goals; Image; Ion Channel; Knockout Mice; Lead; Length; Libraries; Light; Mental Retardation; Methods; Molecular; Neuraxis; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Nuclear Receptors; Pathway interactions; Peptide Hydrolases; Peripheral Nervous System; Pharmaceutical Preparations; Phosphotransferases; Population; Process; Proteins; Reporting; Schizophrenia; Solubility; Staining method; Stains; Synapses; Testing; Therapeutic; Time; Toxic effect; Twin Multiple Birth; United States National Institutes of Health; base; density; high throughput screening; immunocytochemistry; in vitro activity; in vivo; insight; medical specialties; neuron development; response; scale up; small molecule; small molecule libraries; synaptogenesis; tool

DESCRIPTION (provided by applicant): Many major neurodevelopmental disorders, including autism, epilepsy and schizophrenia, are believed to the caused by aberrant synapse formation during brain development, resulting in an excess or deficit of certain classes of synapses. Our long term goal is to understand the molecular mechanisms of synapse formation in the central nervous system (CNS), with the aim of developing therapeutics for these devastating diseases. The process of synapse formation has been best characterized in the peripheral nervous system, where the complete loss of neuromuscular junctions has been reported for multiple single gene knockout mice. In the central nervous system, despite the presence of many proteins that show strong synaptogenic activity in vitro, genetic deletion of several of these proteins result in only subtle changes in synapse density limited to small populations of neurons. These results suggest that the synaptogenic machinery in the CNS is heavily redundant; a situation that makes it inefficient to apply traditional genetic approaches to study the problem. We believe that an unbiased chemical screen for determinants of synapse formation, with its potential to block or enhance key pathways and entire classes of genes, may present a more efficient approach to studying synaptogenic mechanisms in the CNS. In addition, the study may also generate small molecule probes that will be useful in perturbing synapse formation and excitatory-inhibitory balance in vivo. An excess or deficit of specific synapses has been hypothesized to underlie many neurodevelopmental disorders, but to date, these hypotheses have been difficult to prove due to the lack of tools to perturb the underlying network connectivity. We believe our proposal will remedy this situation, and at the same time generate a high impact dataset which will shed light on the mechanisms of synapse formation in the CNS. PUBLIC HEALTH RELEVANCE: Defects in brain development leading to an excess or deficit of synapses may result in neurodevelopmental disorders such as autism, schizophrenia, epilepsy and mental retardation. Currently, no drug exists to directly target the development of synapses in the brain. We propose to screen a large chemical library for compounds that will modulate synapse development in the intact brain, and thereby shed light on the molecular mechanisms of the process as well as provide candidate compounds for both investigative and therapeutic purposes.

描述（由申请人提供）：许多主要的神经发育障碍，包括自闭症、癫痫和精神分裂症，被认为是由大脑发育期间异常的突触形成引起的，导致某些类别的突触过多或不足。我们的长期目标是了解中枢神经系统（CNS）中突触形成的分子机制，目的是为这些毁灭性疾病开发治疗方法。突触形成的过程在外周神经系统中得到了最好的表征，其中已经报道了多个单基因敲除小鼠的神经肌肉接头的完全丧失。在中枢神经系统中，尽管存在许多在体外显示出强突触形成活性的蛋白质，但这些蛋白质中的几种的遗传缺失仅导致突触密度的细微变化，仅限于小群体的神经元。这些结果表明，中枢神经系统中的突触发生机制是严重冗余的;这种情况使得应用传统遗传方法来研究该问题的效率低下。我们认为，一个公正的化学筛选突触形成的决定因素，其潜在的阻断或增强关键途径和整个类的基因，可能会提出一个更有效的方法来研究突触发生机制的中枢神经系统。此外，该研究还可能产生小分子探针，这些探针将用于扰乱体内突触形成和兴奋-抑制平衡。特定突触的过量或不足已被假设为许多神经发育障碍的基础，但迄今为止，由于缺乏干扰潜在网络连接的工具，这些假设一直难以证明。我们相信，我们的建议将纠正这种情况，并在同一时间产生一个高影响力的数据集，这将揭示在中枢神经系统中的突触形成的机制。 公共卫生相关性：大脑发育缺陷导致突触过多或不足，可能导致神经发育障碍，如自闭症、精神分裂症、癫痫和智力迟钝。目前，还没有药物直接针对大脑中突触的发育。我们建议筛选一个大型的化学库的化合物，将调节突触发育的完整的大脑，从而阐明了分子机制的过程，以及提供候选化合物的调查和治疗的目的。